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(Circulation Research. 2000;87:e1.)
© 2000 American Heart Association, Inc.

UltraRapid Communication

A Novel Angiotensin-Converting Enzyme–Related Carboxypeptidase (ACE2) Converts Angiotensin I to Angiotensin 1-9

Mary Donoghue, Frank Hsieh, Elizabeth Baronas, Kevin Godbout, Michael Gosselin, Nancy Stagliano, Michael Donovan, Betty Woolf, Keith Robison, Raju Jeyaseelan, Roger E. Breitbart, Susan Acton

From Millennium Pharmaceuticals, Inc, Cambridge, Mass. Current address for M.G. is Praecis Pharmaceuticals, Cambridge, Mass.

Correspondence to Susan Acton, Millennium Pharmaceuticals, Inc, 75 Sidney St, Cambridge, MA 02139. E-mail acton{at}mpi.com

Abstract—ACE2, the first known human homologue of angiotensin-converting enzyme (ACE), was identified from 5' sequencing of a human heart failure ventricle cDNA library. ACE2 has an apparent signal peptide, a single metalloprotease active site, and a transmembrane domain. The metalloprotease catalytic domains of ACE2 and ACE are 42% identical, and comparison of the genomic structures indicates that the two genes arose through duplication. In contrast to the more ubiquitous ACE, ACE2 transcripts are found only in heart, kidney, and testis of 23 human tissues examined. Immunohistochemistry shows ACE2 protein predominantly in the endothelium of coronary and intrarenal vessels and in renal tubular epithelium. Active ACE2 enzyme is secreted from transfected cells by cleavage N-terminal to the transmembrane domain. Recombinant ACE2 hydrolyzes the carboxy terminal leucine from angiotensin I to generate angiotensin 1-9, which is converted to smaller angiotensin peptides by ACE in vitro and by cardiomyocytes in culture. ACE2 can also cleave des-Arg bradykinin and neurotensin but not bradykinin or 15 other vasoactive and hormonal peptides tested. ACE2 is not inhibited by lisinopril or captopril. The organ- and cell-specific expression of ACE2 and its unique cleavage of key vasoactive peptides suggest an essential role for ACE2 in the local renin-angiotensin system of the heart and kidney. The full text of this article is available at http://www.circresaha.org.

Key Words: angiotensin-converting enzyme • ACE2 • angiotensin • renin-angiotensin system

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